WO1997026021A1 - Procedes, compositions et articles contraceptifs - Google Patents

Procedes, compositions et articles contraceptifs Download PDF

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Publication number
WO1997026021A1
WO1997026021A1 PCT/US1997/000020 US9700020W WO9726021A1 WO 1997026021 A1 WO1997026021 A1 WO 1997026021A1 US 9700020 W US9700020 W US 9700020W WO 9726021 A1 WO9726021 A1 WO 9726021A1
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WIPO (PCT)
Prior art keywords
cysteamine
vaginal
cystamine
compound
phosphocysteamine
Prior art date
Application number
PCT/US1997/000020
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English (en)
Inventor
Jess G. Thoene
Original Assignee
Thoene Jess G
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Thoene Jess G filed Critical Thoene Jess G
Priority to AU18226/97A priority Critical patent/AU1822697A/en
Publication of WO1997026021A1 publication Critical patent/WO1997026021A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
    • A61F6/00—Contraceptive devices; Pessaries; Applicators therefor
    • A61F6/02—Contraceptive devices; Pessaries; Applicators therefor for use by males
    • A61F6/04—Condoms, sheaths or the like, e.g. combined with devices protecting against contagion
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
    • A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
    • A61L2300/408—Virucides, spermicides

Definitions

  • the present invention relates to methods, compositions, and articles, effective for contraception.
  • the contraceptive foam Semicid contains nonylphenoxypolyoxyethene glycol (nonoxynol-9) as a contraceptive agent.
  • nonoxynol-9 is irritating to mucus membranes and can cause cervico-vagmal irritation. This irritation increases the risk of infections, because it causes a disruption of the vaginal and cervical epithelial cell integrity (see Sex. Trans. Pis .. vol. 18, p. 176 (1991) ) . Further studies have shown that nonoxynol-9 is not an effective anti-viral agent (see J. Med. P ⁇ matol. vol. 19, p. 401 1990) ) . Thus, nonoxynol-9 is effective as a contraceptive agent but is irritating to the mucus memoranes and serves to increase the risk of viral infection because of its irritant activity.
  • cysteamine, cystamine, phosphocysteamine, and pharmaceutically acceptable salts thereof are effective contraceptives when topically applied to the vagina or incorporated into, e.g., vaginal suppositories, condom lubricants, vaginal foams, and other barrier-enhancing methods of contraception.
  • the present invention relates to a method of contraception by the vaginal application of an effective amount of cysteamine, cystamine, phosphocysteamine, or a pharmaceutically acceptable salt thereof .
  • Cysteamine is a known compound of the formula
  • Cysteamine may be prepared from ethanolamine and carbon disulfide via 2-mercaptoth ⁇ azolme (Gabriel et al, Ber.. vol. 31, 2837 (1898); Knorr et al, Ber. , vol. 36, 1281 (1903) ; and Mills, Jr. et al, J. Am. Chem. Soc.. vol. 62, 1173 (1940)) or via ethyleneimme ( enker, J. Am. Chem. Soc. , vol. 57, 2328 (1935) ; Mills, Jr. et al, J. A . Chem. Soc.. vol. 62, 1173 (1940) ; and Shirley, Preparation of Organic Intermediates, Wiley, NY, p. 189 (1951)) .
  • Cysteamine is useful for the treatment of nephropathic cystmosis (Thoene et al, The Journal of Clinical Investigation, vol. 58, pp. 180-189 (1976) , Thoene et al, The Journal of Pediatrics, vol. 96, pp. 1043-1044 (1980) ; Thoene, m Orphans Dru ⁇ s and Orphan Diseases: Clinical Realitj.es and
  • Cysteamine also shows good in vi tro activity against HIV.
  • cysteamine at 100 ⁇ M shows excellent protection against HTLVIII 9 with treated cells showing 133% of control survival, and no toxicity (120.8% of control) (Thoene, J., Clm. Res . Abstract. May, 1992)) .
  • Experiments on other cell lines and with other HIV strains substantiate the antiviral effect of cysteamine against HIV and its lack of cellular toxicity at concentrations which completely inhibit the virus.
  • H 2 NCH 2 CH, S 2 and may be prepared by the H : 0 : oxidation of cysteamine (Mills, Jr. et al, . Am. Che . Soc.. vol. 62, 1173 (1940) ; and Barnett, J. Chem. Soc .. 1944, 5) . Cystamine also demonstrates substantial activity against the HIV pathogen, and shows little cytotoxicity at 100 ⁇ M concentration.
  • Phosphocysteamine is the phosphorothioester of cysteamine and has the formula
  • Phosphocysteamine is also known to be useful for the treatment of nephropathic cystmosis (Thoene et al, The Journal of Pediatrics, vol. 96 , pp. 1043-1044 (1980) ; Thoene, in Cooperative Approaches to Research and Development of Crpnan Drugs, Alan R. Liss, NY, pp. 157-162 (1985) ; and S olm et. al . Pediatric Research, vol. 23, pp. 616-620 (1988)1.
  • One r.undred ⁇ M cysteamine caused an apparent two-fold increase in the doubling time and reduced the cloning efficiency to zero (Thoene, J., et al, J. Clin. Invest, vol. 58, pp. 180-189 (1976)) .
  • aqueous cysteamine at concentrations of 0.1% and 0.5%, which correspond to 10 mM and 50 mM, respectively, were used. These concentrations are effective in reducing the cystme crystals found in the corneas of patients witn nephropathic cystmosis, and the drug is well-tolerated in chronic use via this modality.
  • Rabbit studies have snown both concentrations to be safe as evaluated via the Draize test iKaiser-Kupfer, M. et al, Archives of Ophthalmology, vol. 108, pp. 689-693 (1990) , and Kaiser-Kupfer, M. et al, New En ⁇ . , ⁇ Med.. vol. 316, pp. 775-779 (1987)) .
  • the present method involves the vaginal application of cysteamine or a pharmaceutically acceptable salt thereof.
  • the present method involves topical application to the vagina to prevent pregnancy as a result of vagina intercourse.
  • the topical application is carried out prior to the beginning of vaginal intercourse, suitably 0 to 60 minutes, preferably 0 to 5 minutes, prior to the beginning of vaginal intercourse.
  • cysteamine is applied in an amount that will result n a local concentration of 1 mM to 1 M, preferably 2.0 mM to 500 mM, most preferably 5 mM to 100 mM, throughout the vagina.
  • the suitable, preferred, and most preferre ⁇ dosages correspond to the same respective dosages of cysteamine in terms of weight and one half those of cysteamine terms of moles.
  • the suitable, preferred, and most preferred dosages are the same as those of cysteamine in terms of moles.
  • the present compounds are effective as non-spermicidal contraceptives at low concentrations and exhibit spermicidal activity at higher concentrations.
  • the cysteamine may be applied to the vagina in a ⁇ umoer of forms including aerosols, foams, jellies, creams, suppositories, tablets, tampons, etc. Compositions suitable for application to the vagina are disclosed in U.S. Patent Nos.
  • cysteamine cysteamine
  • cystamine cystamine
  • phosphocysteamine or a pharmaceutically acceptable salt thereof
  • additional contraceptive agent which may act either in a spermicidal or non-spermicidal way.
  • additional contraceptives include nonylphenoxypolyoxyethylene glycol (nonoxynol-9) , benzethonium chloride, and chlorindanol .
  • spermicidal active agent other than cysteamine, cystamine, phosphocysteamine, or a pharmaceutically acceptable salt thereof be present in the composition to effect impaired sperm viability. Rather, in some embodiments, no additional spermicidal agent need be present in the composition.
  • cysteamine itself will exhibit spermicidal activity. The higher concentrations may provide a superior contraceptive effect by means of a combination of non-spermicidal and spermicidal contraception.
  • cysteamine has been found to be a potent inhibitor of hyaluronidase and acrosin.
  • the primary mode of action when applied in an amount sufficient to result m a vaginal concentration of less than about 10 mM of cysteamine (or an equivalent amount of cystamine, phosphocysteamine, or pharmaceutically acceptable salt thereof) , the primary mode of action could include hyaluronidase inhibition. At concentrations between about 10 mM and about 300 mM, the primary mode of action could include hyaluronidase inhibition and acrosin inhibition. At concentrations between about 300 mM and 1 M, the primary mode of action could include inhibition of both hyaluronidase and acrosin, as well as spermicidal activity.
  • composition containing the cysteamine, cystamine, phosphocysteamine or pharmaceutically acceptable salt tnereof may be applied to the vagina m any conventional manner Suitable devices for applying the composition to the vagina are disclosed in U.S. Patent Nos. 3,826,828, 4,108,309, 4,360,013, and 4,589,880, which are incorporated herein py reference.
  • the present method also includes administration of mixtures of cysteamine, cystamine, phosphocysteamine, or salts thereof.
  • pharmaceutically acceptable salt thereof refers to any salt of cysteamine, cystamine, or phosphocysteamine which is pharmaceutically acceptable and does not greatly reduce or inhibit the contraceptive effect of cysteamine, cystamine, or phosphocysteamine.
  • Suitable examples include acid addition salts, with an organic or inorganic acid such as acetic acid, tartaric acid, trifluoroacetic acid, lactic acid, aleic acid, fumaric acid, citric acid, methanesulfonic acid, sulfu ⁇ c acid, phosphoric acid, nitric acid, or hydrochloric acid.
  • tr fluoroacetate, nitrate, or methanesulfonate salts in vaginal compositions may not be preferred due to irritation.
  • phosphocysteamine either or both of the hydrogen atoms on the phosphoryl group may be replace ⁇ with any suitable cation, such as Na , K , Mg " , Ca "* , NH, ' , or NR, " (where R is a C . .,, alkyl) .
  • cysteamine cystamine
  • cystamine cystamine
  • phosphocysteamine and pharmaceutically acceptable salts thereof include all the hydrated forms of these compounds as well as the anhydrous forms.
  • an antibacterial or antiviral agent may be coapplied to the vagina along with the cysteamine, cystamine, phosphocysteamine, and/or pharmaceutically acceptable salt thereof.
  • Such antibacterial and antiviral agents are preferably those effective against sexually transmitted diseases and include butylurea (see U.S. Patent No. 5,229,423, which is incorporated herein by reference) and benzalkonium chloride (see U.S. Patent No. 5,387,611, which is incorporated herein by reference) .
  • the present invention also encompasses compositions and articles containing such antibacterial and/or antiviral agents.
  • compositions useful for preventing pregnancy may be in the form of foams, creams, jellies, suppositories, tablets, aerosols, etc. Particularly preferred are vaginal suppositories.
  • concentration of cysteamine, cystamine, phosphocysteamine, or pharmaceutically acceptable salt in the composition is such to achieve the local vaginal concentrations described above upon administration of the usual amount of the type of composition being applied.
  • the suppository will usually be 1 to 5 grams, preferably about 3 grams, and the entire suppository will be applied.
  • a vaginal tablet will suitably be 1 to 5 grams, preferably about 2 grams, and the entire tablet will be applied.
  • the composition is a vaginal cream, suitably 0.1 to 2 grams, preferably about 0.5 grams of the cream will be applied.
  • the composition is a water-soluble vaginal cream, suitably 0.1 to 2 grams, preferably about 0.6 grams, are applied.
  • the composition is a vaginal spray-foam, suitably 0.1 to 2 grams, preferably about 0.5 grams, of the spray-foam are applied.
  • the composition is a vaginal soluble waffle, suitably the waffle is 0.1 to 2 grams, preferably about 0.3 grams, and the entire waffle is applied.
  • the composition also contain a spermicide.
  • suitable spermicides are disclosed in the U.S. Patents cited and incorporated herein by reference above.
  • Preferred spermicides include nonoxynol 9, benzethonium chloride, and chlorindanol.
  • the pH of the composition is 4.5 to 8.5.
  • Vaginal compositions preferably have a pH of 4.5 to 6, most preferably about 5. In the case of phosphocysteamine, the pH is preferably about 7.
  • compositions include in the composition an agent which will mask the taste and/or odor of the cysteamine, cystamine, pnosphocysteamine, and/or pharmaceutically acceptable salt thereof.
  • agents include those flavoring agents and scents typically found compositions intended for vaginal application, such as cinnamon or peppermint oil.
  • compositions may also be in the form of a time-release composition.
  • cysteamine, cystamine, phosphocysteamine, and/or a pharmaceutically acceptable salt thereof is incorporated in a composition which will release cysteamine, cystamine, phosphocysteamine, and/or a pharmaceutically acceptable salt thereof at a rate wnich will result in the vaginal concentration described above.
  • Time-release compositions are disclosed in Controlled Release of Pesticides and Pharmaceuticals. D. H. Lew, Ed., Plenum Press, New York, 1981; and U.S. Patent Nos.
  • the time-release composition when it contains either cystamine or phosphocysteamine, it may oe desiraple to include in the time-release composition an agent whicn is capaple of converting cystamine or phosphocysteamine into cysteamine.
  • the agent may oe any reducing agent capable of converting cystamine to cysteamine, such as glutathione.
  • the agent could be any phosphatase capable of converting phospnocysteamme to cysteamine and which retains its activity the local environment (vagina) such as bovine or human prostatic acid phosphatase or alkaline phosphatase. The use of prostatic acid pnosphatase is preferred.
  • compositions may also be in the form which releases cysteamine, cystamine, phosphocysteamine, and/or a pharmaceutically acceptable salt thereof in response to some event such as vaginal intercourse.
  • the composition may contain cysteamine, cystamine, and/or phosphocysteamine in vesicles or liposomes which are disrupted by the mechanical action of intercourse.
  • Compositions comprising liposomes are described U.S. Patent No. 5,231,112 and Deamer and Uster, "Liposome Preparation Methods and Mechanisms", m Liposomes. pp. 27-51 (1983) ; Sessa et al, J. Biol. Chem. , vol. 245, pp.
  • cystamine and phosphocysteamine it may be desirable to include the composition an agent which will convert the released cystamine and/or phosphocysteamine to cysteamine.
  • compositions may be associated with an article, such as an trauterme device (IUD) , vaginal diaphragm, vaginal sponge, pessary, condom, etc.
  • IUD trauterme device
  • vaginal diaphragm vaginal diaphragm
  • vaginal sponge vaginal sponge
  • pessary pessary
  • condom mechanical-release compositions are preferred.
  • the present invention provides novel articles which are useful for the prevention of pregnancy.
  • the present articles are those which release cysteamine, cystamine, phosphocysteamine, and/or a pharmaceutically acceptable salt thereof when placed in the vagina.
  • the present articles also release an agent capable of converting cystamine or phosphocysteamine into cysteamine.
  • the present invention provides IUDs, vaginal diaphragms, vaginal sponges, pessaries, or condoms which contain or are associated with cysteamine, cystamine, phosphocysteamine, and/or a pharmaceutically acceptable salt thereof or a composition containing cysteamine, cystamine, phosphocysteamine, and/or a pharmaceutically acceptable salt thereof.
  • the present article may be an IUD which contains cysteamine, cystamine, phosphocysteamine, and/or a pharmaceutically acceptable salt thereof.
  • Suitable IUDs are disclosed in U.S. Patent Nos. 3,888,975 and 4,283,325 which are incorporated herein by reference.
  • the present article may be an intravaginal sponge which comprises and releases, in a time-controlled fashion, cysteamine, cystamine, phosphocysteamine, and/or a pharmaceutically acceptable salt thereof .
  • Intravaginal sponges are disclosed in U.S. Patent Nos . 3,916,898 and 4,360,013, which are incorporated herein by reference.
  • the present article may also be a vaginal dispenser which releases cysteamine, cystamine, phosphocysteamine, and/or a pharmaceutically acceptable salt thereof.
  • Vaginal dispensers are disclosed in U.S. Patent No. 4,961,931, which is incorporated herein by reference.
  • the present article may also be a condom which is coated with cysteamine, cystamine, phosphocysteamine, and/or a pharmaceutically acceptable salt thereof.
  • the condom is coated with a lubricant or penetration enhancing agent which comprises cysteamine, cystamine, phosphocysteamine, and/or a pharmaceutically acceptable salt thereof.
  • the lubricant or penetration enhancing agent comprises cysteamine, cystamine, phosphocysteamine, and/or a pharmaceutically acceptable salt thereof which is encapsulated in liposomes such that the cysteamine, cystamine, phosphocysteamine, and/or a pharmaceutically acceptable salt thereof is released from the liposomes upon intercourse.
  • Lubricants and penetration enhancing agents are described in U.S. Patent Nos. 4,537,776; 4,552,872; 4,557,934; 4,130,667, 3,989,816; 4,017,641; 4,954,487; 5,208,031; and 4,499,154, which are incorporated herein by reference.
  • cysteamine, cystamine, phosphocysteamine, and/or a pharmaceutically acceptable salt thereof is contained inside the condom.
  • cysteamine, cystamine, phosphocysteamine, and/or a pharmaceutically acceptable salt thereof is contained in a reservoir the tip of the condom.
  • compositions according to the invention which contain cysteamine.
  • composition for a 3-gram suppository Composition for a 3-gram suppository:
  • composition for a 2-gram tablet Composition for a 2-gram tablet:
  • composition for one 0.340-gram waffle Composition for one 0.340-gram waffle:
  • polyethylene glycol 1000 65.0 polyethylene glycol 300 NF 3.0 cellulose 1.0 alginic acid (80 mesh) 15.0 sodium bicarbonate (100 mesh) 12.0 Cysteamine 4.0
  • This composition is prepared as follows.
  • the two polyethylene glycols are melted together at a temperature of about 62°-68 c C
  • the cysteamine is adde ⁇ to the melt under an atmosphere of N with agitation, the agitation being continued for sufficient time to totally mix the ingredients, usually from about 5 to 10 minutes.
  • the celi ⁇ lose is then dispersed into the mixture under slow-speed agitation, after which first the sodium bicarbonate and then the algmic acid is added. Agitation is continued for about 15 to 30 minutes to completely disperse the latter ingredients into tne mixture. During this period, the temperature _s maintained substantially constant.
  • the mass is cooled to about 52°C and is then poured in torpedo-shaped molds which have been pre-chilled to about 15°-20°C.
  • the molds are then placed m freezing cabinets until the mass is thoroughly chilled.
  • the products are thereafter removed from the molds, ready for use or storage.
  • Example 1-7 The above ingredients are mixed together in the manner described Example 1-7 and treated at the temperature and for tne periods described in Example 1-7.
  • composition is prepared by mixing all the ingredients under an atmosphere of , with approximately 90% of the required water and allowing the polyoxyethylene- polyoxypropylene block copoly er to hydrate and completely dissolve w th gentle stirring When a clear gel is obtained, the remaining water is added to adjust the volume to 100 ml.
  • Hyaluronidase activity is quantified by measuring the extent of hyaluronic acid hydrolysis This is measured by determining the concentration of N-acetylglucosamme-reactive material, resulting from enzyme action.
  • Reaction mixtures contain the following, in a total volume of 0.25 ml: 0.1 M sodium acetate, containing 0.15 M NaCl, pH 5.5 (Acetate buffer) , 7.2 Units sheep testicular hyaluronidase (Sigma, Type III, cat no. H-2251) , from a stock solution dissolved in the Acetate buffer; 0.3 mg/ml hyaluronic acid (Sigma, from bovine vitreous humor, cat-no. H-763C, .
  • the test compound is screened at a concentration cf 1 mg/ml, unless aqueous solubility is limited.
  • the enzyme is pre cubated with the test agent for 10 minutes prior to starting the reaction by adding hyaluronic acid. Enzyme reactions are determined by the method of Aronson and Davidson (J. Biol. Chem.. vol. 242, pp. 437-440 (1967)) . Incubations are carried out for 30 minutes at ambient temperature. Reaction product is determined colorimetrically after reaction with p-dimethylaminobenzaldehyde (Reissig et al. , J. Biol. Chem.. vol. 217, pp. 959-966 (1955)) . The absorbance cf the resultant adduct is immediately determined at 545 nm.
  • IC 50 values are - 24 '
  • This value is the average of all blank values, as follows: absorbance readings were 0.0376, 0.0514, 0.0507, 0.0415 and 0.0497 for blanks containing 0, 1.6, 8, 40, 200 and 1,000 ⁇ g/ml cysteamine, respectively. - 26 -
  • the extract is concentrated by ultrafiltration (Amicon PM 10) and applied to a column that contains Sephadex G-150 (superfine) ; elution is carried out with 55 mM acetic acid that contains 0.1 M NaCl.
  • the eluted volume that contains acrosin activity is pooled and used as the source of enzyme.
  • Enzyme reaction mixtures contain the following: 50 mM sodium pnosphate, pH 7.5 (Anderson et al, Arch. Biochem. Biopnys .. vol. 241, pp. 509-520 (1985)) ; Enzyme-containing protein (3-5 mlU, where 1 mlU is the amount of enzyme required to hydrolyze 1 nmole BAEE per min) ; 0.05 mM BAEE; with or without inhibitor, in a total volume of 1.0 ml.
  • test compound is screened at a concentration cf l mg/ml, unless solubility is limited.
  • the enzyme is premcubated with the test agent for 5 minutes prior to starting the reaction by adding BAEE. Reaction blanks, which either substrate or enzyme has been eliminated, are run in parallel to the reactions.
  • the rate of change in absorbance at 253 nm is determined.
  • the change in absorbance that corresponds to 1 ⁇ mole of BAEE (in a total volume of 1.0 ml) hydrolyzed is taken as 1.15.
  • the enzyme activity in the presence of each agent is compared with that for the control reaction (no test agent added) .
  • the data are reported as % inhibition.
  • Compounds that show no activity at the screening concentration of 1 mg/ml are considered to be inactive.
  • a dose-response curve is generated at several concentrations of test compound if significant inhibition is obtained at the screening concentration.
  • Reversibility of acrosin inhibition is determined by the method of Ackermann and Potter (Proc. Soc. Exp. Biol. Med.. vol. 72, pp. 1-9 (1949)) , in which the level of inhibited enzyme activity is determined in the presence of different amounts of enzyme. The data so obtained are consistent with a reversible mechanism of inhibition of human acrosin by cysteamine.
  • IC 50 values are determined by analyzing enzyme activity as a function of inhibitor concentration, with curve-fitting software (TableCurve 2D, version 3.02; Jandel Scientific) . ⁇ 2 8 -
  • the method is based on that originally described by Sander and Cramer (F.V Sander and S.D. Cramer. Human Fertil .. vol c, pp. 134 (1941)) Apparent spermicidal activity of the test agents are compared to that of a control preparation of nonoxynol-9 (N9)
  • a solution of 50 mg/ml is prepared in 0.9% NaCl This solution is adjusted to pH 7.0 with either HCl or NaOH and is further diluted 0.9% NaCl to concentrations of 25 mg/ml, 10 mg/ml, 5 mg/ml, and 2.5 mg/ml.
  • N9 is prepared as a solution of 100 ⁇ g/ml 0.9% NaCl.
  • the agents are tested by mixing 40 ⁇ l of freshly ejaculated semen with 200 ⁇ l of test agent at each concentration. Just prior to and 30 seconds after mixing, the percentage of motile spermatozoa is determined by microscopic observation (400 x) . If 90-100% inhibition of motility is obtained at the lowest concentration tested, the experiment is repeated with a different range of concentrations, the iighest concentration being 2.5 mg/ml. A dose-response curve is constructed.
  • test outcome is reported as the concentration of agent in the semen sample that reduces motility by 50% and wnere possible, the lowest concentration of agent that (virtually) completely inhibits motility. • 30-
  • cysteamine was found to reduce sperm motility. Although cysteamine was found to be less effective than nonoxynol-9 as a spermicide on a weight basis, cysteamine may be used in high amounts, because it is well tolerated (see results on the effects on normal vaginal flora below) . Thus, cysteamine may be used as a spermicide at higher concentrations.
  • Cysteamine was screened with regard to its potential cytotoxicity toward normal vaginal flora. Growth of vaginal lactobacillus was used as a measure of this effect.
  • Lactobacillus gasseri obtained from the American Type
  • Dose-response curves are produced by determining the doubling time of the culture in the presence of each of several concentrations of test agent, the exact range of which is determined by the results of the screening test that is described above.
  • concentration of test agent that inhibits the growth of lactobacillus by 50% IC 50
  • IC 50 concentration of test agent that inhibits the growth of lactobacillus by 50%
  • cysteamine had no effect on the propagation of lactobacillus at a concentration of 5 mg/ml, indicating that it would be well tolerated in humans for this usage .

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  • Veterinary Medicine (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Biomedical Technology (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention concerne l'application vaginale de cystéamine, de cystamine, de phosphocystéamine, ou de l'un de leurs sels galéniques, ces produits étant particulièrement efficaces en tant que contraceptifs.
PCT/US1997/000020 1996-01-16 1997-01-16 Procedes, compositions et articles contraceptifs WO1997026021A1 (fr)

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AU18226/97A AU1822697A (en) 1996-01-16 1997-01-16 Methods, compositions and articles for contraception

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US08/585,100 US5725870A (en) 1993-10-15 1996-01-16 Methods, composites and articles for contraception
US08/585,100 1996-01-16

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JP3012923B2 (ja) * 1998-01-26 2000-02-28 新潟大学長 Ｃａｇリピート病の治療薬
AR057623A1 (es) 2005-11-28 2007-12-05 Omega Bio Pharma H K Ltd Materiales y metodos para el tratamiento de las infecciones virales

Citations (1)

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Publication number Priority date Publication date Assignee Title
US5260054A (en) * 1992-01-10 1993-11-09 Helene Curtis, Inc. Cysteamine permanent wave composition and method

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US3892824A (en) * 1968-12-16 1975-07-01 Southern Res Inst S-{107 -({107 -aminoalkylamino)alkyl dihydrogen phosphorothioates
IT1055560B (it) * 1974-05-02 1982-01-11 Istituto Chemioterapico Derivati pirimidinici e relative composizioni per il trattamento di infezioni virali
CA1157774A (fr) * 1980-07-30 1983-11-29 Anthony Cerami Methode pour diminuer la viscosite de la mucine
US4885285A (en) * 1984-09-13 1989-12-05 Ciba-Geigy Corporation Phosphorus compounds, processes for their manufacture, and their use
EP0204989B1 (fr) * 1985-06-08 1992-03-25 ASTA Medica Aktiengesellschaft Utilisation de la pénicillamine pour le traitement des maladies d'immuno-dépression
CA1339256C (fr) * 1989-01-26 1997-08-12 Wulf Droge Traitement de maladies associees aux infections par le vih
EP0473673A4 (en) * 1989-05-24 1995-05-17 Us Bioscience Method for protection from azt side effects and toxicity
US5554655A (en) * 1991-09-30 1996-09-10 Jess G. Thoene Method of treating HIV infection
MX9205549A (es) * 1991-09-30 1993-05-01 Jess G Thoene Metodo para el tratamiento de vih.
WO1994004185A2 (fr) * 1992-08-19 1994-03-03 Trustees Of Boston University Procede pour inhiber la reduction de ponts disulfure

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5260054A (en) * 1992-01-10 1993-11-09 Helene Curtis, Inc. Cysteamine permanent wave composition and method

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US5725870A (en) 1998-03-10

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